Process for the manufacture of unsaturated compounds



PROCESS I! THE MANUFACTURE OI UNSATUBA'IED COMPOUNDS Walter Huber. Basel. Bwitserland, assigns to lloilmann-La Roche Inc., Kelley, N. 1., a corporation of New Jersey No Drawing. Application June 18, 1041. Serial No. 766,504. In lwltaerland December 81. 10

1 I Claims- (Ol. sec-em This invention relates to the manufacture oi with a compound easily splitting oil iodine in orunsaturated compounds. and more especially of der to bring about allyl rearrangement and delow alkyl ethers oi vitamin A and dehydro-vitahydration. min A. l-alkoxy-8.7-dymethyl-6-hydroxy-9-trimethyl- It is Lnown that vitamin A ether-e may precycloheaenyl-nonatriene-(2,4,7) (I) or l-alkozypared synthetically by condensing 4-(2.6'.6'- afl-dimethyl-d-hydr xy 9 trimethyloyolchem" trimethylcyclohexene-(l'i-yl) -2-methyl-buteneenyl-nonadiene-flm-yne-(dl (IV) are used as (2)-al-(l) with a Grignard-compound oi l-alstarting materials for the present process. The koxy-t-methyl-pentme-(fl)-yne-(4). subiecting preparation or these compounds may be eilected the Milton-3.7-dymethyl-8-hydrmry-9-trimeth- 10 according to the indications given in the papers ylcyclohexeynl-nonadiene-(2,'l)-yne-(4) formed cited above. The course or the reaction is to catalytic hydrogenation until 1 mol oi hydrodeemed to follow the iormulae hereafter:

CHI CHI 0ni-cn=-E-cu-cn-oa-i-cn-cmoa m-on-E-hB-orso-E-cn-omoa I: m Ha Be l W cm on on cm on on on-:a-c-oncn-cn -cn-omon m-bn-i-cn-cac-i-cn-omoit' I Ha Ha Ha Ks OH: Hi

I: l v

CHI OBI OH: OBI

oa=on-Z=ca-cn=cn- -on-omon a-on-o-cn-ozo z-oa-omon B Ba Be Hi It gen has been added to the triple-bond of said It stands tor a low alkyl group.

hydroxy compound, and heating the i-alkoxy- The compounds obtained (in and VI) are vita- 3,7- dimethyl-il -hydroxy- 9 -trimethylcyclcheaemin A-alkyl ether or dehydro-ritamin A ether. nyi-nonetriene-(SAJ) thus obtained with a small respectively. The latter compound may be transproportion oi iodine (compare Experientia. vol. formed into vitamin A alkyl ether by partial 11, year 1946, page 91; I'estschriit iiir Emil Barell. hydrogenation of the triple-bond. year 1946, mge 31). The sequence oi the par- As in the known process, using iodine. allyl retlal hydrogenation and the treatment with iodine arrangement and dehydration occur in one remay be inverted. action step ii the starting materials are treated. It has now been found. according to the present according to the present invention, with a cominvcntion. that in the said process iodine may be a pound containing loosely bound iodine. Such replaced by compounds which easily split at! iodine compounds are. ior example. phosphorus iodine. Thus, the present specification provides iodides. hydrogen iodide and halogen iodides. for a process tor the manuiacture or unsaturated lurthcrmore metalloid iodides. such as arscnic compounds, comprising reacting a compound of and antimony iodides and organic compounds. the formula 0 such as iodine-pyridine complex compounds on on (e. g.. I(pyridine):.N0s) or carbon tetra-iodide.

In order to eilect allyl rearrangement and dehydration, the starting materials, preferably in the presence 0! a diluent. are heated with one of the on C Hr-O H-O n-x-z-otl-o 810R said iodine compounds. Thus. allyl rearrangement and dehydration may be carried out in wherein n pyridine solution at 0' C. by means oi an equivalent quantity oi phosphorus (ll-iodide. An adstands tor a radical selected from the group vantageous method consists in heating the startconsisting of CH=CH- and -CarC, and m lng materials in an inert solvent having its boil- R. represents a low alkyl radical, ing point between -140 0. with a small quantity of the iodine compound. Petroleum ether of boiling range 110-110 C. has provedto be a suit- Example 1 1 part by weight of 1-methoxy-3,'i-dimethyl- 6-hydroxy-0-trimethylcyclohexenyl nonatriene- (2,4,7) in 20 parts by volume of petroleum ether of boiling range -110 C. is refluxed while stirring and introducing nitrogen. 0.02 part by weight of flnely pulverised phosphorus di-iodide (Pals) are added in the course of minutes to the boiling solution. Refiuxing is continued ior 15 minutes; after cooling down, the mixture is diluted with petroleum ether of boiling range 30-00 C. and then repeatedly shaken with 95 per cent. methyl alcohol. While the dehydration products (about 0.? part by weight) remain in the petroleum ether. unchanged starting material (about 0.3 part by weight) migrates into the methyl alcohol, from which it may be isolated in the usual manner and then reacted in boiling petroleum ether with-phosphorus di-iodide in the said manner. The petroleum ether solutions. containing the products resulting from allyl rearrangement and dehydration are washed with water. dried with sodium sulfate and boiled down. A crude product containing -45 per cent. of vitamin A methyl other is obtained.

This product may be purified, for example by a percolation chromatogram on to columns of weakly active aluminium oxide by means of petroleum ether of boiling range oil-80 C. Intermediates. having a free hydroxy group, adhere to the aluminium oxide, whereas by-products, absorbing light of lower wave lengths (280-290 mg) concentrate in the flrst runnings. Vitamin A methyl ether slowly migrates through the column during which process the position thereof may easily be ascertained by the intensive yellowgreen fluorescence in ultra-violet light. The desired fraction is characterised by the stability of the Carr-Price-color reaction and by the high refraction of the residue. The purified vitamin A ether thus obtained is a yellow oil, boiling at 00-95" C. under a pressure of 10" mm. Hg. The compound proves to cause in the absorption spectrum the maximum at 320 m typical for vitamin A, and to possess high biological activity.

Example 2 4 parts by weight of 1-methoxy-3,7-dimethyl- B-hydroxy-O-trimethylcyclohexenyl nonatriene- (2,4,7) are dissolved in 20 parts by volume of dry pyridine and 3 parts by weight of finely pulverised phosphorus di-iodide (Pam are added at 0 C. in several portions while stirring and introducing nitrogen. Stirring at 0 C. is continued for 1 hour whereupon petroleum ether of boiling range 30-60 C. is added. The solution is successively shaken out with ice-cold l-normal sulfuric acid and sodium bicarbonate and water.

4 The petroleum ether solution is then dried with sodium sulfate and boiled down. A crude product containing 10-15 per cent. of vitamin A methyl ether is obtained and may be purified in accordance with Example 1.

Example 8 1 part by weight of l-methoxy-3,7-dirnethyi- 6-hydroxy-9-trimethylcyclohexem'l nonatriene- (2,4,7) is refluxed in 20 parts by volume of petroleum ether of boiling range 00-110 C. while introducing nitrogen and stirring. 0.04 part by weight of 50 per cent. aqueous hydrogen iodide are added in several portions. The mixture is refluxed for another 15 minutes, left to cool down and worked up in accordance with Example 1. A crude product containing 40-50 per cent. oi vitamin A methyl other is obtained and may be purified in accordance with the directions given in Example 1.

Example 4 1 part by weight of 1-methoxy-3,'l-dimethyi- 6-hydroiw-ii-trimethylcyclohexenyl nonatriene- (2.4.7) is refluxed in 20 parts by volume of petroleum ether of boiling range -110 C. while introducing nitrogen and stirring. 0.02 part by weight of chlorine iodide in 3 parts by volume of petroleum ether of boiling range 80-110 C. are added in the course of 5 minutes. The mixture is refluxed for another 15 minutes. cooled down and worked up in accordance with Example 1. A crude, product containing 30-40 per cent. of vitamin A methyl ether is obtained and may be purifled in accordance with Example 1.

Bromine iodide may be used in the above example in place of chlorine iodide, whereby vitamin A methyl other is obtained in equal yield.

Example 5 1 part by weight of 1-methoxy-3,7-dimethyl-6- hydroxy A) trimethylcyclohexenyl nonatriene- (2,4,7) is refluxed in 20 parts by volume of petroleum ether of boiling range 80-110 C. while introducing nitrogen and stirring. 0.05 part by weight of Iipyridine) :.N0a are added to the boilin! solution in several portions. The mixture is refluxed and stirred for 15 minutes. left to cool down and worked up according to Example 1. A crude product, containing 20-30 per cent. of vitamin A methyl ether, is obtained and may be purified according to the directions given in Example 1.

Example 6 10 parts by weight of 1-methoxy-3,7-dimethyl- B-hydroxy-Q-trimethylcyclohexenyl nonadiene- (2.7) -yne-(4) are refluxed in 200 parts by volume of petroleum ether of boiling range 80-110 C. while introducing nitrogen and stirring. 0.2 part by weight of flnely pulverized phosphorus diiodide (P214) are added to the boiling solution in the course of 5 minutes. Stirring and refluxing are continued for 15 minutes; then the mixture is left to cool down, diluted with petroleum ether of boiling range 50-60 C. and repeatedly shaken out with per cent. methyl alcohol. While the dehydration products (about 5 parts by weight) remain in the petroleum ether, unchanged starting material (about 5 parts by weight) migrates into the 95 per cent. methyl alcohoiand may be isolated therefrom in the usual manner and again treated in boiling petroleum other with phosphorus di-iodide. The petroleum ether solution containing the products of the dehydration is washed with water, dried with sodium sulfate and boiled down. '7 to 8 parts by weight of a yellow oil are obtained, the main part of which proves to consist of 1-methoxy-3,l-dimethyl-Q-trimethylcyclohexenyl-nonatriene- (2,6,8) -yne-(4) (dehydro-vitamin A methyl ether) which. by partial hydrogenation at the triple-bond, may be transformed into vitaminA methyl ether.

I claim:

1. Process for the manufacture or unsaturated compounds, comprising reacting a compound of the formula wherein X stands for a radical selected from the group consisting of --CH=CH- and -CEC, and R represents a low aikyl radical, with an iodo compound easily splitting oil iodine in order to bring about aliyl rearrangement and dehydration.

2. Process in accordance with claim 1. comprising using 1-metho1cv-3,7-dimethyl-6-hydroxy-9- trimethylcyclohexenyl nonatriene (2,4,7) as starting material and eflecting the reaction in an inert solvent 0! boiling range 80-140 0.

Certificate Patent No. 2,451,741.

. REFERENCES CITED The following references are of record in the file of this patent:

Johnson, Acetylenic Compounds. vol. I (pages 234-5) (1946).

Experimentia, vol. III (page 31) (1946); Fastschrift flir Emil Barell, (page 31) (1946).

of Correction October 19, 1948.

WALTER HUBER It is hereby certified that errors appear in the numbered patent requiring correction as follows:

printed specification of the above Column 1, line 10, for dymothyl" read dimethyl; line 59, for C," read 0-,; column 2, line 4, for dymethyl read dimethyl; and that the said Letters Patent should be read with these corrections therein that the same may conform to the record of the case in the Patent Office.

Signed and sealed this 8th day of February, A. D. 1949.

THOMAS F. MURPHY,

Assistant Commissioner of Patents.

boiled down. '7 to 8 parts by weight of a yellow oil are obtained, the main part of which proves to consist of 1-methoxy-3,l-dimethyl-Q-trimethylcyclohexenyl-nonatriene- (2,6,8) -yne-(4) (dehydro-vitamin A methyl ether) which. by partial hydrogenation at the triple-bond, may be transformed into vitaminA methyl ether.

I claim:

1. Process for the manufacture or unsaturated compounds, comprising reacting a compound of the formula wherein X stands for a radical selected from the group consisting of --CH=CH- and -CEC, and R represents a low aikyl radical, with an iodo compound easily splitting oil iodine in order to bring about aliyl rearrangement and dehydration.

2. Process in accordance with claim 1. comprising using 1-metho1cv-3,7-dimethyl-6-hydroxy-9- trimethylcyclohexenyl nonatriene (2,4,7) as starting material and eflecting the reaction in an inert solvent 0! boiling range 80-140 0.

Certificate Patent No. 2,451,741.

. REFERENCES CITED The following references are of record in the file of this patent:

Johnson, Acetylenic Compounds. vol. I (pages 234-5) (1946).

Experimentia, vol. III (page 31) (1946); Fastschrift flir Emil Barell, (page 31) (1946).

of Correction October 19, 1948.

WALTER HUBER It is hereby certified that errors appear in the numbered patent requiring correction as follows:

printed specification of the above Column 1, line 10, for dymothyl" read dimethyl; line 59, for C," read 0-,; column 2, line 4, for dymethyl read dimethyl; and that the said Letters Patent should be read with these corrections therein that the same may conform to the record of the case in the Patent Office.

Signed and sealed this 8th day of February, A. D. 1949.

THOMAS F. MURPHY,

Assistant Commissioner of Patents. 

